Nitric oxide is a ubiquitous messenger implicated in several important signalling pathways. Critical physiological functions such as regulation of the vascular tone, immune response and neuromodulation depend on dynamics. In between its synthesis (by synthases or by chemical reduction of nitrite) and its inactivation (by heme globins or oxidation to nitrite and nitrate), diffuses trough biological milieu reaching its molecular targets.
Considered for long as waste product, capable of induce gastric cancer via the formation of carcinogenic nitrosamines, nitrite is now proving that is more than a stable NO metabolite. Nitrite represents a vast reservoir in the body and has been implicated in many modulatory pathways itself. The nitrite biology gained attention upon the report of production in the stomach from inorganic nitrite. Nitrate from diet is reduced to nitrite in the saliva that reaches the gastric lumen where the acidic pH promotes the univalent reduction to, in the so-called nitrate-nitrite- pathway. This pathway originates the highest yield of in vivo. Several enzymes have been shown to acquire nitrite reductase properties at low oxygen tensions, suggesting a role for nitrite in the hypoxic signalling.
In the gastrointestinal tract, nitrite-derived has been shown to modulate host defence, blood flow, mucus production and gastric motility and protection. At the acidic pH, nitrite generates several nitrogen oxides (RNOS) beside such as nitrogen dioxide and dinitrogen trioxide (N2O3) that can induce post-translational modifications of endogenous proteins with physiological impact. Other dietary components with redox potential such as red wine polyphenols are known to be implicated in the nitrite chemistry in the gastric lumen, enhancing production by univalent reduction of nitrite and consequent oxidation of the polyphenols to its o-semiquinone radical.
The work presented in this thesis shows that dietary nitrite is able to induce nitrosation (mostly S-nitrosation) of mucus glycoproteins (mucins) and in the gastric mucosa cells, pointing towards -mediated actions in the mucosa and to the filter effect of the mucus. This pattern is redox-modulated by red wine, suggesting novel actions for wine polyphenols in vivo via the balance of S- an N-nitroso compounds in the gastric wall. A highly sensitive chemiluminescence methodology was used to quantify the formation of nitroso compounds. S-nitrosothiols are fairly stable compounds that may act as carriers and exert both local and systemic impact. In fact, nitrosated mucus from rat stomach with acidified nitrite is shown to release at physiological pH. The alteration of the gastric environment by inflammation in vivo shows to increase nitrite induced nitrosation, particularly the S-nitrosothiols fraction.
Alongside with mucus production and blood flow regulation, dietary nitrite and its derivatives demonstrated to contribute for the maintenance of gastric mucosal integrity via the stimulation of the expression of an important signaling peptide, the trefoil factor 1 (TFF1) involved mucosal protection and anti-tumorigenesis. Again, the redox modulation of the nitrite chemistry by red wine plays an important role, particularly under inflammatory conditions, by increasing TFF1 expression.
The high concentration of nitrite and achieved in the stomach raised the question of how can gastric mitochondria cope with such challenge. Mitochondrial is a known target for and more recently was identified as a target for nitrite also. In fact, it was observed in these results that not only gastric mitochondria can deal with both and nitrite amounts easily achieved by a vegetables rich diet, but also mitochondrial function is improved with the nitrate-nitrite pathway. The analysis of mitochondrial function was achieved recurring to high-resolution oxygraphy. Mitochondria are key in cell function and signaling, and the modulation of their functionality by dietary derived inorganic molecules such as nitrite and can have major effects in gastric physiology and disease.
Taken together, these results highlight the relevance of bioactive compounds in everyday diet such as nitrate and nitrite, their interaction with other diet components as red wine and their impact in the gastric physiopathology.

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FCT - SFRH/BD/62265/2009

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eng

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openAccess

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nitrito

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nitrite

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fisiologia gástrica

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vinho tinto

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óxido nítrico

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gastric physiology

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red wine

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nitric oxide

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dc.title

The role of nitrite-derived nitric oxide in gastric physiology: biochemical mechanisms, molecular targets and the modulatory effect of red wine